Articular cartilages are responsible for providing moveable joints the ability for smooth gliding motion. The articular cartilages are firmly attached to the underlying bones and measure less than 5 mm in thickness in human joints, with considerable variation depending on joint and site within the joint. The articular cartilages are aneural, avascular, and alymphatic. In adult humans, they derive their nutrition by a double diffusion system through the synovial membrane and through the dense matrix of the cartilage to reach the chondrocyte.
The biochemical composition of articular cartilage includes up to 65-80% water (depending on the cartilage), with collagen as the most prevalent organic constituent. Articular cartilage consists of highly specialized chondrocytes surrounded by a dense extracellular matrix consisting mainly of type II collagen, proteoglycan and water. Collagen (mainly type II) accounts for about 15-25% of the wet weight and about half the dry weight, except in the superficial zone where it accounts for most of the dry weight. Its concentration is usually progressively reduced with increasing depth from the articular surface. The proteoglycan content accounts for up to 10% of the wet weight or about a quarter of the dry weight. Proteoglycans consist of a protein core to which linear sulfated polysaccharides are attached, mostly in the form of chondroitin sulfate and keratin sulfate. In addition to type II collagen, articular collagen contains several other collagen types (IV, V, IX and X) with distinct structures. There are a variety of interactions between these individual macromolecules, which include both noncovalent associations between proteoglycans and collagens, and covalent bonds between different collagen species. Resistance of the extracellular matrix to water flow gives cartilage its ability to dispense high joint loads. It absorbs shock and minimizes stress on subchondral bone (Mow et al., 1984, J. Biomech. 17:377-394). Adult cartilage and bone have a limited ability of repair.
Damage of cartilage produced by disease, such as rheumatoid and/or osteoarthritis, or trauma can lead to serious physical deformity and debilitation. As human articular cartilage ages, its tensile properties change. The superficial zone of the knee articular cartilage exhibits an increase in tensile strength up to the third decade of life, after which it decreases markedly with age as detectable damage to type II collagen occurs at the articular surface. The deep zone cartilage also exhibits a progressive decrease in tensile strength with increasing age, although collagen content does not decrease. These observations indicate that there are changes in mechanical and, hence, structural organization of cartilage with aging that, if sufficiently developed, can predispose cartilage to traumatic damage. In osteoarthritic cartilage there is excessive damage to type II collagen, resulting in crimping of collagen fibrils. In rheumatoid arthritis, the combined actions of free radicals and proteinases released from polymorpholeukocytes cause much of the damage seen at the articular surface. (Tiku et al., 1990, J. Immunol. 145:690-696). Induction of cartilage matrix degradation and proteinases by chondrocytes is probably induced primarily by interleukin-1 (IL-1) or tumor necrosis factor-.alpha. (TNF-.alpha.) (Tyler, 1985, Biochem. J. 225:493-507).
The current therapy for loss of cartilage is replacement with a prosthetic material, for example, silicone for cosmetic repairs, or metal alloys for joint relinement. Placement of prosthetic devices is usually associated with loss of underlying tissue and bone without recovery of the full function allowed by the original cartilage. Serious long-term complications associated with the presence of a permanent foreign body can include infection, erosion and instability.
Use of sterilized bone or bone powder or surgical steel seeded with bone cells which were eventually implanted have been largely unsuccessful because of the non-degradable nature of the cell support. According to one procedure fibroblasts are exposed in vitro for a minimum of three days, to a soluble bone protein capable of stimulating in vitro and/or in vivo a chondrogenic response. The activated fibroblasts are then transferred in vivo by combining them with a biodegradable matrix, or by intra-articular injection or attachment to allografts and prosthetic devices. The disadvantage of this method is that chondrogenesis is not allowed to develop in the short-term cultures and there is an unduly heavy reliance for cartilage synthesis by the exposed fibroblasts at the implant site. Caplan, A., U.S. Pat. No. 4,609,551, issued Sep. 2, 1986.
U.S. Pat. No. 5,041,138 to J. P. Vacanti et al., issued Aug. 20, 1991, describes growth of cartilaginous structures seeding chondrocytes on biodegradable matrices for subsequent implantation in vivo. Although this system offers the advantage of a greater surface area and exposure to nutrients, the conditions employed for culturing the chondrocytes are routine and no efforts have been made to optimize the conditions for the chondrocytes to produce collagen and other cartilage-type macromolecules.